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Background: Elevated apoB-containing lipoproteins (=remnants+LDLs [low-density lipoproteins]) are a major risk factor for atherosclerotic cardiovascular disease, including peripheral artery disease (PAD) and myocardial infarction. We tested the hypothesis that remnants and LDL both explain part of the increased risk of PAD conferred by elevated apoB-containing lipoproteins. For comparison, we also studied the risk of chronic limb-threatening ischemia and myocardial infarction., Methods: apoB, remnant cholesterol, and LDL cholesterol were measured in 93 461 individuals without statin use at baseline from the Copenhagen General Population Study (2003-2015). During up to 15 years of follow-up, 1207 had PAD, 552 had chronic limb-threatening ischemia, and 2022 had myocardial infarction in the Danish National Patient Registry. Remnant and LDL cholesterol were calculated from a standard lipid profile. Remnant and LDL particle counts were additionally measured with nuclear magnetic resonance spectroscopy in 25 347 of the individuals. Results were replicated in 302 167 individuals without statin use from the UK Biobank (2004-2010)., Results: In the Copenhagen General Population Study, multivariable adjusted hazard ratios for risk of PAD per 1 mmol/L (39 mg/dL) increment in remnant and LDL cholesterol were 1.9 (95% CI, 1.5-2.4) and 1.1 (95% CI, 1.0-1.2), respectively; corresponding results in the UK Biobank were 1.7 (95% CI, 1.4-2.1) and 0.9 (95% CI, 0.9-1.0), respectively. In the association from elevated apoB to increased risk of PAD, remnant and LDL cholesterol explained 73% (32%-100%) and 8% (0%-46%), respectively; corresponding results were 63% (30%-100%) and 0% (0%-33%) for risk of chronic limb-threatening ischemia and 41% (27%-55%) and 54% (38%-70%) for risk of myocardial infarction; results for remnant and LDL particle counts corroborated these findings., Conclusions: PAD risk conferred by elevated apoB-containing lipoproteins was explained mainly by elevated remnants, while myocardial infarction risk was explained by both elevated remnants and LDL., Competing Interests: Disclosures B.G. Nordestgaard reports consultancies and talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, Abbott, Silence Therapeutics, USV, Mankind, Lilly, Arrowhead, and Marea. The other authors report no conflicts.

Purpose of Review: To review recent advances in the field of remnant lipoproteins and remnant cholesterol with a focus on cardiovascular disease risk., Recent Findings: In line with previous years' research, current observational, genetic, and mechanistic studies find remnant lipoproteins (defined in different ways) to be involved in atherosclerosis development and cardiovascular disease risk. High concentrations of remnant cholesterol could explain some of the residual risk of cardiovascular disease seen after LDL cholesterol lowering. This will be increasingly important as populations worldwide become more obese and more have diabetes, both of which elevate remnant cholesterol concentrations. Many smaller scale studies and post hoc analyses show that remnant cholesterol can be lowered by different types of drugs; however, results from large scale studies with the primary aim of reducing cardiovascular disease risk through lowering of remnant cholesterol in individuals with elevated concentrations are still missing, although some are under way., Summary: Remnant cholesterol is a risk factor for cardiovascular disease, and can be lowered by different types of drugs; however, large scale studies of cardiovascular disease risk reduction through remnant lipoprotein lowering are under way.

Objective: Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD)., Approach and Results: Arterial wall inflammation and bone marrow activity were measured using 18 F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of 18 F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 [0.27-0.40]; P <0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], P =0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of 18 F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing., Conclusions: Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD., (© 2017 American Heart Association, Inc.)

Scientific interest in triglyceride-rich lipoproteins has fluctuated over the past many years, ranging from beliefs that these lipoproteins cause atherosclerotic cardiovascular disease (ASCVD) to being innocent bystanders. Correspondingly, clinical recommendations have fluctuated from a need to reduce levels to no advice on treatment. New insight in epidemiology now suggests that these lipoproteins, marked by high triglycerides, are strong and independent predictors of ASCVD and all-cause mortality, and that their cholesterol content or remnant cholesterol likewise are strong predictors of ASCVD. Of all adults, 27% have triglycerides >2 mmol/L (176 mg/dL), and 21% have remnant cholesterol >1 mmol/L (39 mg/dL). For individuals in the general population with nonfasting triglycerides of 6.6 mmol/L (580 mg/dL) compared with individuals with levels of 0.8 mmol/L (70 mg/dL), the risks were 5.1-fold for myocardial infarction, 3.2-fold for ischemic heart disease, 3.2-fold for ischemic stroke, and 2.2-fold for all-cause mortality. Also, genetic studies using the Mendelian randomization design, an approach that minimizes problems with confounding and reverse causation, now demonstrate that triglyceride-rich lipoproteins are causally associated with ASCVD and all-cause mortality. Finally, genetic evidence also demonstrates that high concentrations of triglyceride-rich lipoproteins are causally associated with low-grade inflammation. This suggests that an important part of inflammation in atherosclerosis and ASCVD is because of triglyceride-rich lipoprotein degradation and uptake into macrophage foam cells in the arterial intima. Taken together, new insights now strongly suggest that elevated triglyceride-rich lipoproteins represent causal risk factors for low-grade inflammation, ASCVD, and all-cause mortality., (© 2016 American Heart Association, Inc.)

Background and Purpose: We tested the hypothesis that observationally and genetically elevated YKL-40 is associated with elevated lipids and lipoproteins and with increased risk of ischemic vascular disease., Methods: We conducted cohort and Mendelian randomization studies in 96 110 individuals from the Danish general population, with measured plasma levels of YKL-40 (n=21 647), plasma lipids and lipoproteins (n=94 461), and CHI3L1 rs4950928 genotype (n=94 579)., Results: From 1977 to 2013, 3256 individuals developed ischemic stroke, 5629 ischemic cerebrovascular disease, 4183 myocardial infarction, and 10 271 developed ischemic heart disease. The 91% to 100% versus 0% to 33% YKL-40 percentile category was associated with a 34% increase in triglycerides, but only with minor changes in other lipids and lipoproteins. For these categories, the multifactorially adjusted hazard ratio was 1.99 (95% confidence interval, 1.49-2.67) for ischemic stroke, 1.85 (1.44-2.37) for ischemic cerebrovascular disease, 1.28 (0.95-1.73) for myocardial infarction, and 1.23 (1.01-1.51) for ischemic heart disease. When compared with rs4950928 CC homozygosity, the presence of G-allele was associated with a doubling (GC) or tripling (GG) in YKL-40 levels, but not with triglyceride levels or with risk of ischemic vascular disease. A doubling in YKL-40 was associated with a multifactorially adjusted observational hazard ratio for ischemic stroke of 1.18 (1.11-1.27), and a genetic odds ratio of 1.04 (0.95-1.15). Corresponding risk estimates were 1.15 (1.09-1.22) observationally and 1.06 (0.99-1.14) genetically for ischemic cerebrovascular disease, 1.08 (1.00-1.15) observationally and 1.04 (0.96-1.13) genetically for myocardial infarction, and 1.07 (1.02-1.12) observationally and 1.01 (0.96-1.07) genetically for ischemic heart disease., Conclusions: Elevated YKL-40 was associated with a 34% increase in triglyceride levels and with a 2-fold increased risk of ischemic stroke, whereas genetically elevated YKL-40 were not., (© 2015 American Heart Association, Inc.)

Purpose of Review: To review recent advances in the field of remnant cholesterol as a contributor to the development of ischemic heart disease (IHD)., Recent Findings: Epidemiologic, mechanistic, and genetic studies all support a role for elevated remnant cholesterol (=cholesterol in triglyceride-rich lipoproteins) as a contributor to the development of atherosclerosis and IHD. Observational studies show association between elevated remnant cholesterol and IHD, and mechanistic studies show remnant cholesterol accumulation in the arterial wall like LDL-cholesterol (LDL-C) accumulation. Furthermore, large genetic studies show evidence of remnant cholesterol as a causal risk factor for IHD independent of HDL-cholesterol levels. Genetic studies also show that elevated remnant cholesterol is associated with low-grade inflammation, whereas elevated LDL-C is not. There are several pharmacologic ways of lowering remnant cholesterol levels; however, it remains to be seen in large randomized clinical intervention trials if lowering of remnant cholesterol, in individuals with elevated levels, will reduce the risk of IHD., Summary: Evidence is emerging for elevated remnant cholesterol being a causal risk factor for IHD. Elevated remnant cholesterol levels likely are part of the explanation of the residual risk of IHD observed after LDL-C has been lowered to recommended levels.

Background: Elevated nonfasting remnant cholesterol and low-density lipoprotein (LDL) cholesterol are causally associated with ischemic heart disease (IHD), but whether elevated nonfasting remnant cholesterol and LDL cholesterol both cause low-grade inflammation is currently unknown., Methods and Results: We studied 60 608 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease study, of whom 10 668 had IHD diagnosed between 1977 and 2011. We genotyped for variants affecting levels of nonfasting remnant cholesterol, LDL cholesterol, C-reactive protein by CRP alleles, and C-reactive protein by IL6R alleles. Using a multidirectional mendelian randomization design, we investigated possible causal associations between the lipoproteins and C-reactive protein and between the lipoproteins and IHD. A 1-mmol/L(39 mg/dL) higher level of nonfasting remnant cholesterol was associated observationally with a 37% (95% confidence interval, 35-39) higher C-reactive protein level and causally with a 28% (95% confidence interval, 10-48) higher level. For LDL cholesterol, a 1-mmol/L (39-mg/dL) higher level was associated observationally with a 7% (95% confidence interval, 6-7) higher C-reactive protein level, but we found no causal association. Likewise, higher levels of C-reactive protein did not associate causally with elevated nonfasting remnant cholesterol or LDL cholesterol. Finally, the causal risk ratio for IHD for a 1-mmol/L (39-mg/dL) higher level was 3.3 (95% confidence interval, 2.1-5.2) for nonfasting remnant cholesterol and 1.8 (95% confidence interval, 1.5-2.2) for LDL cholesterol. The causal associations for remnant cholesterol were present even in those without diabetes mellitus and obesity., Conclusions: Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, whereas elevated LDL cholesterol is associated causally with IHD without inflammation.

Purpose of Review: To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance of such genetic determinants with cardiovascular disease risk will either favor or disfavor that these lipoproteins are causally related to cardiovascular disease., Recent Findings: Evidence for concordance or discordance with cardiovascular disease risk has come from Mendelian randomization studies, whereas indirect evidence also has emerged from genome-wide and candidate gene association studies. The major limitations of studies of genetic variation and concordance or discordance with cardiovascular disease are pleiotropic effects of the variants studied, and/or lack of sufficient statistical power of the majority of studies to firmly demonstrate a positive association, or even more difficult, to exclude an association., Summary: New and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), and triglyceride-rich lipoproteins are concordant with both the magnitude and direction of the expected risk of cardiovascular disease, whereas this is unclear for HDL cholesterol. The data are compatible with cardiovascular disease causality for the three former lipoprotein classes, but not for HDL cholesterol.